Our current research focuses on patients with motor neuron disorders, particularly disorders affecting corticospinal (upper) motor neurons such as primary lateral sclerosis (PLS). It has been proposed that PLS, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are related disorders that represent different phenotypes on the same spectrum of neurodegenerative disorders. Pathological studies by other investigators found the same proteins within neuronal inclusions in brains of ALS and a subset of FTD patients, and in genetic studies, a mutation in the gene C9ORF72 was recently found to account for a significant portion of familial ALS and FTD. It has been hypothesized that PLS is a variant of these disorders in which the degenerative process remains largely limited to the motor cortex, failing to progress to frontotemporal cortex and the spinal cord. If this hypothesis is correct, understanding what limits the extent of disease in PLS patients may provide clues to mechanisms for halting progression of neurodegeneration. The first aim of this project is to understand the relationship between PLS and other disorders on the motor neuron disease spectrum. To determine whether clinical phenotypes are a function of the brain regions undergoing degeneration, work over the last few years has utilized quantitative magnetic resonance imaging (MRI). During FY13, we completed and published an analysis of white matter tracts associated with cognitive performance in ALS and PLS patients, using a semi-automated atlas-based analysis to compare diffusion tensor imaging (DTI) measures in eleven white matter association tracts. Changes in diffusivity measures in the superior longitudinal fasciculus, cingulum, and portions of the corpus callosum were found to be associated with performance on particular executive function and memory tests. Performance was not related to focal changes in grey matter volume, highlighting the importance of the integrity of axonal tracts for proper temporal encoding of information in cognitive networks. In collaboration with the NINDS Cognitive Neuroscience section, we are now extending that work to include comparisons with FTD patients studied with the same methods, with a goal of identifying imaging measures that discriminate between patients with different diagnoses and clinical presentations. We have also begun examining whether other non-motor manifestations, such as pseudobulbar affect, can be explained by alterations in particular white matter networks. To examine the question whether disease begins focally in PLS and spreads thorough axonal networks or by propagation to adjacent areas of the brain and spinal cord, we began a chart review of the cohort of PLS patients followed in our clinic to document how symptoms spread. A second aim of the project is to identify reliable, non-invasive markers for detection and measuring progression of brain involvement in motor neuron disorders. During FY13, we published a longitudinal MRI study in ALS and PLS patients that found that changes in DTI metrics and measures of cortical thickness and atrophy progress over different time scales. We hypothesized that MRI findings represent a sequence of structural changes that occur with axonal breakdown and clearance, followed by measureable thinning and atrophy of cortical grey matter. Differences between ALS and PLS patient groups may represent early and late stages of the same process, with longer time for structural remodeling to evolve in PLS patients. Changes in white matter DTI measures occurred relatively early. We are currently looking to see whether functional MRI resting state networks show alterations in motor neuron disease, and will be assessing whether functional changes can be detected earlier than changes in diffusion measures. To date, most imaging studies in motor neuron disease describe differences between groups of patients and controls. It is a challenge to develop imaging measures that are indicators of the state of upper motor neuron integrity in individual patients. As a first step, we are currently obtaining multi-modal imaging in repeated sessions in a cohort of healthy controls in order to determine the intersession variability of candidate imaging markers. These data will be used to select the most informative techniques for prospectively assessing patients with motor neuron disorders in the future. In addition to the two primary aims of this project, we participated in two collaborative studies in FY13. We continued as a site in a collaborative study to examine the role of oxidative stress in progression of motor neuron diseases organized by Columbia University. The study was fully enrolled at our site and all patients completed their annual visits. Two patients completed the entire study, and our site is on track for completion in two years. Additionally, we began a new collaboration with the NINDS Section on Infections of the Nervous System to look for evidence of endogenous retroviruses in motor neuron disease patients. Lastly, in collaboration with the NIA Neuromuscular Diseases Section, we have laid the groundwork for a natural history and biomarker study of symptomatic and presymptomatic carriers of the C9ORF72 gene mutation. The human subject research protocol has now been approved by the IRB and we anticipate enrollment of the first patient before the end of FY13.